Pulmonology Department, Cattinara Hospital, University of Trieste, 34127 Trieste, Italy.
Department of Medical Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy.
Cells. 2022 Jun 30;11(13):2095. doi: 10.3390/cells11132095.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with unknown etiology in which gradual fibrotic scarring of the lungs leads to usual interstitial pneumonia (UIP) and, ultimately, to death. IPF affects three million people worldwide, and the only currently available treatments include the antifibrotic drugs nintedanib and pirfenidone, which effectively reduce fibrosis progression are, unfortunately, not effective in curing the disease. In recent years, the paradigm of IPF pathogenesis has shifted from a fibroblast-driven disease to an epithelium-driven disease, wherein, upon recurrent microinjuries, dysfunctional alveolar type II epithelial cells (ATII) are not only unable to sustain physiological lung regeneration but also promote aberrant epithelial-mesenchymal crosstalk. This creates a drift towards fibrosis rather than regeneration. In the context of this review article, we discuss the most relevant mechanisms involved in IPF pathogenesis with a specific focus on the role of dysfunctional ATII cells in promoting disease progression. In particular, we summarize the main causes of ATII cell dysfunction, such as aging, environmental factors, and genetic determinants. Next, we describe the known mechanisms of physiological lung regeneration by drawing a parallel between embryonic lung development and the known pathways involved in ATII-driven alveolar re-epithelization after injury. Finally, we review the most relevant interventional clinical trials performed in the last 20 years with the aim of underlining the urgency of developing new therapies against IPF that are not only aimed at reducing disease progression by hampering ECM deposition but also boost the physiological processes of ATII-driven alveolar regeneration.
特发性肺纤维化（IPF）是一种慢性、进行性的间质性肺疾病（ILD），其病因不明。在这种疾病中，肺部逐渐纤维化瘢痕形成导致普通间质性肺炎（UIP），最终导致死亡。IPF 影响全球 300 万人，目前唯一可用的治疗方法包括抗纤维化药物尼达尼布和吡非尼酮，这些药物虽然能有效减缓纤维化进展，但不幸的是并不能治愈这种疾病。近年来，IPF 发病机制的范式已经从成纤维细胞驱动的疾病转变为上皮细胞驱动的疾病，在这种疾病中，反复的微损伤会导致功能失调的肺泡 II 型上皮细胞（ATII）不仅无法维持生理肺再生，而且还会促进异常的上皮-间充质相互作用。这导致疾病向纤维化而不是再生方向发展。在本文中，我们讨论了与 IPF 发病机制相关的最相关的机制，特别关注功能失调的 ATII 细胞在促进疾病进展中的作用。具体来说，我们总结了 ATII 细胞功能失调的主要原因，如衰老、环境因素和遗传决定因素。接下来，我们通过比较胚胎肺发育和已知的 ATII 驱动肺泡再上皮化途径，描述了生理肺再生的已知机制。最后，我们回顾了过去 20 年中进行的最相关的干预性临床试验，目的是强调开发针对 IPF 的新疗法的紧迫性，这些疗法不仅旨在通过抑制 ECM 沉积来减缓疾病进展，而且还能促进 ATII 驱动的肺泡再生的生理过程。
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